Markusse et al. Arthritis Research & Therapy (2015) 17:171 DOI 10.1186/s13075-015-0681-7
LETTER
Open Access
Response to ‘Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis’ – authors’ reply Iris M. Markusse1*, Willem F. Lems2,3, Tom W.J. Huizinga1 and Cornelia F. Allaart1 See related research by Markusse et al., http://arthritis-research.com/content/16/5/430, and related letter by Vastesaeger et al., http://dx.doi.org/10.1186/s13075-015-0680-8
We thank our colleagues for their response, confirming that tailored treatment in rheumatoid arthritis patients is an important topic to address [1]. Current guidelines promote the use of prognostic factors in treatment decisions [2], but perspectives on the predicted outcome vary. Although current treatment strategies suppress radiographic progression in most patients, rapid clinical improvement (RCI) remains relevant for functional restoration [3]. We aimed to predict RCI in patients with a poor prognosis (PP) and with a nonpoor prognosis (non-PP). We based classification on prognostic factors mentioned in the European League Against Rheumatism recommendations (method 1) [2] and, for confirmation, on the Visser model (method 2), despite its focus on predicting rapid radiographic progression (RRP) [4]. We did not aim to compare both methods for superiority, but as our colleagues propose this approach we need to reiterate some of the numbers to accomplish accurate interpretation of our results. First, of the PP patients following Visser’s model (defined as having >50 % RRP risk) receiving initial monotherapy (iMono), 46 % (not 64 %, as our colleagues mention) in fact developed RRP (Table S1 in [5]). As concluded previously, this model predicts RRP better than method 1, in which 26 % of PP patients developed RRP. However, we were interested in predicting RCI.
Second, the separation in the Health Assessment Questionnaire for PP patients versus non-PP patients treated with initial combination therapy (iCombo) (Figure S1 in [5]) is 0.11 to 0.13 per time point; that is, not clinically relevant differences [6]. However, relevant differences in the Health Assessment Questionnaire were shown after 3 months, when comparing iMono with iCombo both in PP and in non-PP patients using methods 1 and 2 (Table S1 in [5]). Last, our colleagues attempt to compare both methods for predicting American College of Rheumatology 20/ 50/70 response on iCombo or on iMono in PP patients and non-PP patients. However, all odds ratios listed were determined with Visser’s method. Odds ratios determined using method 1 (Table 1) were not published previously. Comparing methods 1 and 2, the 95 % confidence intervals are largely overlapping, making it impossible to conclude that one method is superior in predicting American College of Rheumatology response without advanced statistics. These results indicate that, regardless of the method, both PP patients and non-PP patients benefit from iCombo, achieving RCI (Table 1). We maintain that with currently known predictors it is still impossible to define a subgroup that will achieve equal RCI on iMono as that on iCombo. Future research may reveal prognostic factors enabling us to stratify pa-
* Correspondence: [email protected] 1 Department of Rheumatology, Leiden University Medical Center, C-01-R, PO BOX 9600, 2300 RC Leiden, The Netherlands Full list of author information is available at the end of the article © 2015 Markusse et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Markusse et al. Arthritis Research & Therapy (2015) 17:171
Page 2 of 2
Table 1 Odds ratios for achieving ACR response after 3 months for patients treated with initial combination therapy compared with initial monotherapy Method 1
Method 2 (Visser model)
Odds ratio
95 % confidence interval
Odds ratio
95 % confidence interval
ACR20
3.94
2.09 to 7.43
10.00
3.41 to 29.32
ACR50
6.29
3.00 to 13.20
9.74
3.22 to 29.49
ACR70
7.08
2.31 to 21.70
9.33
1.97 to 44.21
ACR20
3.12
1.73 to 5.63
2.72
1.67 to 4.45
ACR50
6.25
3.08 to 12.70
5.39
2.98 to 9.74
ACR70
6.39
1.84 to 22.23
4.99
1.85 to 13.46
Poor prognosis patients
Nonpoor prognosis patients
ACR, American College of Rheumatology
tients for differential treatment. In the meantime, more patients achieve RCI on iCombo than on iMono. This may constitute overtreatment if aiming to prevent future radiographic damage, but prevents undertreatment of debilitating arthritis already present. Abbreviations iCombo: initial combination therapy; iMono: initial monotherapy; non-PP: Nonpoor prognosis; PP: Poor prognosis; RCI: Rapid clinical improvement; RRP: Rapid radiographic progression. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Rheumatology, Leiden University Medical Center, C-01-R, PO BOX 9600, 2300 RC Leiden, The Netherlands. 2Department of Rheumatology, VU Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. 3 Department of Rheumatology, Reade, location dr. Jan van Breemenstraat, PO Box 58271, 1040 HG Amsterdam, The Netherlands.
References 1. Vastesaeger N, Fautrel B, Smolen J. Response to ‘Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis’. Arthritis Res Ther. 2015. 2. Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509. 3. Neovius M, Simard JF, Klareskog L, Askling J, ARTIS Study Group. Sick leave and disability pension before and after initiation of antirheumatic therapies in clinical practice. Ann Rheum Dis. 2011;70:1407–14. 4. Visser K, Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Ronday HK, Seys PEH, Kerstens PJSM, et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the Best study. Ann Rheum Dis. 2010;69:1333–7. 5. Markusse IM, de Vries-Bouwstra JK, Han KH, van der Lubbe PAHM, Schouffoer AA, Kerstens PJSM, et al. Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis. Arthritis Res Ther. 2014;16:430. 6. Pope JE, Khanna D, Norrie D, Ouimet JM. The minimally important difference for the Health Assessment Questionnaire in rheumatoid arthritis clinical practice is smaller than in randomized controlled trials. J Rheumatol. 2009;36:254–9.
LETTER
Open Access
Response to ‘Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis’ – authors’ reply Iris M. Markusse1*, Willem F. Lems2,3, Tom W.J. Huizinga1 and Cornelia F. Allaart1 See related research by Markusse et al., http://arthritis-research.com/content/16/5/430, and related letter by Vastesaeger et al., http://dx.doi.org/10.1186/s13075-015-0680-8
We thank our colleagues for their response, confirming that tailored treatment in rheumatoid arthritis patients is an important topic to address [1]. Current guidelines promote the use of prognostic factors in treatment decisions [2], but perspectives on the predicted outcome vary. Although current treatment strategies suppress radiographic progression in most patients, rapid clinical improvement (RCI) remains relevant for functional restoration [3]. We aimed to predict RCI in patients with a poor prognosis (PP) and with a nonpoor prognosis (non-PP). We based classification on prognostic factors mentioned in the European League Against Rheumatism recommendations (method 1) [2] and, for confirmation, on the Visser model (method 2), despite its focus on predicting rapid radiographic progression (RRP) [4]. We did not aim to compare both methods for superiority, but as our colleagues propose this approach we need to reiterate some of the numbers to accomplish accurate interpretation of our results. First, of the PP patients following Visser’s model (defined as having >50 % RRP risk) receiving initial monotherapy (iMono), 46 % (not 64 %, as our colleagues mention) in fact developed RRP (Table S1 in [5]). As concluded previously, this model predicts RRP better than method 1, in which 26 % of PP patients developed RRP. However, we were interested in predicting RCI.
Second, the separation in the Health Assessment Questionnaire for PP patients versus non-PP patients treated with initial combination therapy (iCombo) (Figure S1 in [5]) is 0.11 to 0.13 per time point; that is, not clinically relevant differences [6]. However, relevant differences in the Health Assessment Questionnaire were shown after 3 months, when comparing iMono with iCombo both in PP and in non-PP patients using methods 1 and 2 (Table S1 in [5]). Last, our colleagues attempt to compare both methods for predicting American College of Rheumatology 20/ 50/70 response on iCombo or on iMono in PP patients and non-PP patients. However, all odds ratios listed were determined with Visser’s method. Odds ratios determined using method 1 (Table 1) were not published previously. Comparing methods 1 and 2, the 95 % confidence intervals are largely overlapping, making it impossible to conclude that one method is superior in predicting American College of Rheumatology response without advanced statistics. These results indicate that, regardless of the method, both PP patients and non-PP patients benefit from iCombo, achieving RCI (Table 1). We maintain that with currently known predictors it is still impossible to define a subgroup that will achieve equal RCI on iMono as that on iCombo. Future research may reveal prognostic factors enabling us to stratify pa-
* Correspondence: [email protected] 1 Department of Rheumatology, Leiden University Medical Center, C-01-R, PO BOX 9600, 2300 RC Leiden, The Netherlands Full list of author information is available at the end of the article © 2015 Markusse et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Markusse et al. Arthritis Research & Therapy (2015) 17:171
Page 2 of 2
Table 1 Odds ratios for achieving ACR response after 3 months for patients treated with initial combination therapy compared with initial monotherapy Method 1
Method 2 (Visser model)
Odds ratio
95 % confidence interval
Odds ratio
95 % confidence interval
ACR20
3.94
2.09 to 7.43
10.00
3.41 to 29.32
ACR50
6.29
3.00 to 13.20
9.74
3.22 to 29.49
ACR70
7.08
2.31 to 21.70
9.33
1.97 to 44.21
ACR20
3.12
1.73 to 5.63
2.72
1.67 to 4.45
ACR50
6.25
3.08 to 12.70
5.39
2.98 to 9.74
ACR70
6.39
1.84 to 22.23
4.99
1.85 to 13.46
Poor prognosis patients
Nonpoor prognosis patients
ACR, American College of Rheumatology
tients for differential treatment. In the meantime, more patients achieve RCI on iCombo than on iMono. This may constitute overtreatment if aiming to prevent future radiographic damage, but prevents undertreatment of debilitating arthritis already present. Abbreviations iCombo: initial combination therapy; iMono: initial monotherapy; non-PP: Nonpoor prognosis; PP: Poor prognosis; RCI: Rapid clinical improvement; RRP: Rapid radiographic progression. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Rheumatology, Leiden University Medical Center, C-01-R, PO BOX 9600, 2300 RC Leiden, The Netherlands. 2Department of Rheumatology, VU Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. 3 Department of Rheumatology, Reade, location dr. Jan van Breemenstraat, PO Box 58271, 1040 HG Amsterdam, The Netherlands.
References 1. Vastesaeger N, Fautrel B, Smolen J. Response to ‘Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis’. Arthritis Res Ther. 2015. 2. Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509. 3. Neovius M, Simard JF, Klareskog L, Askling J, ARTIS Study Group. Sick leave and disability pension before and after initiation of antirheumatic therapies in clinical practice. Ann Rheum Dis. 2011;70:1407–14. 4. Visser K, Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Ronday HK, Seys PEH, Kerstens PJSM, et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the Best study. Ann Rheum Dis. 2010;69:1333–7. 5. Markusse IM, de Vries-Bouwstra JK, Han KH, van der Lubbe PAHM, Schouffoer AA, Kerstens PJSM, et al. Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis. Arthritis Res Ther. 2014;16:430. 6. Pope JE, Khanna D, Norrie D, Ouimet JM. The minimally important difference for the Health Assessment Questionnaire in rheumatoid arthritis clinical practice is smaller than in randomized controlled trials. J Rheumatol. 2009;36:254–9.
